Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Abstract

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated while iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in 7 subjects; no causative mutation was found in the eighth. Biopsies from 4 subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in 1 subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the 2 subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and peri-lesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

CDG and immune response: From bedside to bench and back

“…GALNT3 mutations are among the causes of hyperphosphatemic familial tumoral calcinosis (MIM: 211900). In a subset of GALNT3‐CDG patients, auto‐immune and inflammatory manifestations have been found . In a cohort of seven patients, five showed diaphysitis, four had signs of ectopic calcifications and chronic inflammation, while three exhibited manifestations of overwhelming systemic inflammation.…”

Hyperphosphatemic Familial Tumoral Calcinosis With Galnt3 Mutation: Transient Response to Anti‐Interleukin‐1 Treatments

“…We report on a case of HFTC, complicated by severe inflammatory flares, which is a previously described complication of the disease . The hypothesis of an auto‐inflammatory‐like syndrome is suggested by the clinical and biological presentation, its tendency to evolve through inflammatory flares, and enhanced by the reported presence of macrophages on biopsies of patients with HFTC .…”

“…The hypothesis of an auto‐inflammatory‐like syndrome is suggested by the clinical and biological presentation, its tendency to evolve through inflammatory flares, and enhanced by the reported presence of macrophages on biopsies of patients with HFTC . With this rationale, the effect of anti‐IL‐1 treatment has been reported so far only in two cases, one treated with anakinra, 100 mg subcutaneously daily, then twice daily, and the other one with canakinumab 100 mg every 8 weeks, ie, a sixfold lower dose than the one we used. Both patients had an improvement of general health, a long‐term reduction of CRP, and better action of hypophosphatemic therapies.…”

“…We report on a case of HFTC, complicated by severe inflammatory flares, which is a previously described complication of the disease. (12)(13)(14) The hypothesis of an auto-inflammatory-like syndrome is suggested by the clinical and biological presentation, its tendency to evolve through inflammatory flares, and enhanced by the reported presence of macrophages on biopsies of patients with HFTC. (7) With this rationale, the effect of anti-IL-1 treatment has been reported so far only in two cases, (12) one treated with anakinra, 100 mg subcutaneously daily, then twice daily, and the other one with canakinumab 100 mg every 8 weeks, ie, a sixfold lower dose than the one we used.…”

Clinical Utility Gene Card For: GALNT3 defective congenital disorder of glycosylation

“…At least sixty-six genetically confirmed patients (from 42 families) have been reported [1][2][3]. The frequency and the prevalence of the disease are not known.…”